Use of rasagiline for the treatment of restless legs syndrome

ABSTRACT

Disclosed are methods for the treatment of Restless Legs Syndrome comprising administering an amount of R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof.

This application is a continuation of U.S. Ser. No. 14/524,993, filedOct. 27, 2014, which is a continuation of U.S. Ser. No. 11/731,493,filed Mar. 30, 2007, which claims benefit of U.S. ProvisionalApplication No. 60/788,617 filed Apr. 3, 2006, the entire contents ofeach of which in their entireties are hereby incorporated by reference.

Throughout this application various publications, published patentapplications and published patents are referenced. The disclosures ofthese publications in their entireties are hereby incorporated byreference into this application in order to more fully describe thestate of the art to which this invention pertains.

BACKGROUND OF THE INVENTION

Restless Legs Syndrome (“RLS”, also known as Ekbom Syndrome) is aneurological condition that expresses itself as an overwhelming urge tomove the legs, usually caused by uncomfortable or unpleasant sensationsin the legs at rest. Movement of the legs temporarily alleviates thediscomfort. (Jones et al., Restless Legs Syndrome—A Review, Eur. J.Vasc. Endovasc. Surg., December 1997, 14(6):430-2)

The sensations occur during periods of inactivity, and are thus mostintense in the evening and at night. RLS often causes difficulty stayingor falling asleep, which leads to feelings of daytime tiredness orfatigue. RLS may cause involuntary jerking of the limbs during sleep andsometimes during wakefulness. Because of the nature of these symptoms,RLS is one of the most prevalent causes of sleep disorders such as sleepdisturbance and insomnia. (Fox, G. N., Restless Legs Syndrome, AmericanFamily Physician, January 1986, 33(1):147-52)

RLS can occur at any age but increases in frequency as persons growolder. (Thorpy J. Michael. New Paradignms in the treatment of restlesslegs syndrome. Neurology 2005; 64: S28-S33) It afflicts about 8% of thegeneral population. (see, rls.org/)

At least 80% of RLS patients experience periodic leg movements (PLMs),stereotyped, repetitive flexion movements of the legs that occurapproximately every 5-90 seconds when the patient is asleep or lyingdown resting. (Hening A Wayne et al. An update on the dopaminergictreatment of restless legs syndrome and periodic limb movement disorder.Sleep 2004, 27: 560-583.) Both the sensations in the limbs and the PLMscan profoundly disrupt sleep (getting to sleep and staying asleep). Thiscan lead to excessive daytime sleepiness as well as depression andanxiety and may have a significant negative impact on quality of life.

Treatment of RLS can be difficult and often requires trying differentdrugs and dosage regimes. (The Merck Manual, 17th Ed. 1999, 1416) Theprimary pharmacologic treatment of RLS is principally with two classesof medications: dopaminergic agents and opiate agents. (Restless LegsSyndrome Foundation, Inc. Medical Bulletin, April 2004, pg. 15)

Nearly all patients with RLS show at least an initial positivetherapeutic response to dopamine precursor levodopa (L-dopa) (eitheralone or with a dopa decarboxylase inhibitor like carbidopa) at dosagesvery low compared with those prescribed in the treatment of Parkinson'sdisease. (Montplaisir J. et al., Restless Legs Syndrome and PeriodicMovements in Sleep: Physiopathology and Treatment with L-dopa, Clin.Neuropharmacol., 1986, 9(5):456-463) This initial response, however, isnot universally maintained. The drawback of L-dopa therapy lies in thefact that in many patients its effectiveness tapers off and/or the RLSproblem is shifted toward the morning hours (rebound) or the disorder isaggravated with the problem occurring event during the day(augmentation). (Guilleminault C. et al., Dopaminergic Treatment ofRestless Legs and Rebound Phenomenon, Neurology, 1993, 43(2):445; andAllen R. P., Augmentation of the Restless Legs Syndrome withCarbidopa/Levodopa, Sleep, 1996, 19(3):205-213)

Dopamine-receptor agonists such as pergolide and pramipexole, known bythe trade name Mirapex [available from Boehringer IngelheimPharmaceuticals, Inc., Ridgefield, Conn.], provide well-established andeffective treatment for RLS. However, they have been reported to causemajor side effects. (Dooley M. et al., Pramipexole: A Review of Its Usein the Management of Early and Advanced Parkinson's Disease, DrugsAging, June 1998, 12(6):495-514; and Silber M. H. et al., Pergolide inthe Management of Restless Legs Syndrome: An Extended Study, Sleep,1997, 20(10):878-882) In fact, all of the dopamine agonists can be usedto treat RLS but with a negative aspect in that, usually in thebeginning and as a function of the dosage administered, they lead tosuch side effects as nausea, vomiting, dizziness, hypotension,constipation or insomnia. (Medical Bulletin, infra at pg. 17)

Opiates are effective against RLS as well, although often at relativelyhigh doses. (Walters, A. S. et al., Successful Treatment of theIdiopathic Restless Legs Syndrome in a Randomized Double-Blind Trial ofOxycodone Versus Placebo, Sleep, 1993, 16(4):327-332) However, becauseof the risk of addiction and progressive tolerance these substances aresuitable for therapeutic application to a limited extent at best.

Benzodiazepines such as clonazepam and anticonvulsants such asgabapentin and carbamazepine have also been shown to alleviate thesymptoms of RLS. (Medical Bulletin, infra at pg. 19) However, sideeffects similar to those associated with the treatments described abovelimit use. Addiction and daytime sedation are problematic withbenzodiapenes, which does not prevent movement but only preventsawakening. (Id.) High dosages are required in anticonvulsant treatments.Furthermore, it is thought that anticonvulsants fail to resolve the fullspectrum of elements of RLS. (Telstad W. et al., Treatment of theRestless Legs Syndrome with Carbamazepine; A Double Blind Study, Br.Med. J. (Clin. Res. Ed.), 1984, 288(6415):444-446)

Valproate has also shown benefit for RLS, but the side effect of weightgain has limited its acceptance. (Dinesin H. et al., Weight Gain DuringTreatment With Valproate, Acta. Neurol. Scan., 1984, 70(2):65-69)

Clonidine, originally developed as an antihypertensive agent and miotic,has also been examined for its effectiveness in the treatment of RLS.While it was found that soporiferous latency was reduced, it had noeffect on the quality of sleep, the frequency of waking up or periodicleg movement during sleep. Given that more efficacious substances areavailable for monotherapy, clonidine is not currently recommended as analternative form of therapy except in limited situations. (U.S. PatentPublication No. 2001/0053777, published Dec. 20, 2001)

Therefore, there exists a need for an effective, alternative treatmentand related treatment regime options for individuals who are afflictedwith RLS. More particularly, there exists a need for treatments that donot induce the unwanted effects observed in modern therapeutics of RLS.

SUMMARY OF THE INVENTION

This subject invention provides a method of treating a subject sufferingfrom Restless Legs Syndrome which comprises administering to the subjectan amount of R(+)-N-propargyl-1-aminoindan or a pharmaceuticallyacceptably salt thereof, effective to treat the subject.

The subject invention also provides a method of alleviating a symptom ofRestless Legs Syndrome in a subject afflicted with Restless LegsSyndrome comprising administering to the subject an amount ofR(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable saltthereof effective to alleviate the symptom of Restless Legs Syndrome inthe subject.

The subject invention also provides a pharmaceutical compositioncomprising in unit dosage form R(+)-N-propargyl-1-aminoindan or apharmaceutically acceptable salt thereof and at least one of pergolide,pramipexole, oxycodone, clonazepam, carbamazepine, gabapentin,valproate, ropinirole or clonidin.

The subject invention also provides a pharmaceutical composition for usein the treatment of, or alleviation of symptoms of, Restless LegsSyndrome, which comprises a therapeutically effective amount ofR(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier.

The subject invention also provides use of R(+)-N-propargyl-1-aminoindanor a pharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of, or alleviation of symptoms of, RestlessLegs Syndrome.

The subject invention also provides a pharmaceutical compositioncomprising in unit dosage form R(+)-N-propargyl-1-aminoindan or apharmaceutically acceptable salt thereof and pramipexole.

DETAILED DESCRIPTION

The subject invention provides a method of treating a subject sufferingfrom Restless Legs Syndrome which comprises administering to the subjectan amount of R(+)-N-propargyl-1-aminoindan or a pharmaceuticallyacceptably salt thereof, effective to treat the subject.

The subject invention also provides a method of alleviating a symptom ofRestless Legs Syndrome in a subject afflicted with Restless LegsSyndrome comprising administering to the subject an amount ofR(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable saltthereof effective to alleviate the symptom of Restless Legs Syndrome inthe subject.

In an embodiment, the symptom may be any of tingling in the legs, crampsin the legs, pain in the legs or restlessness in the legs.

In the methods, the IRLS Rating Scale score of the subject decreasescompared to the baseline.

In an embodiment of the methods, the decrease is a 20% decrease,preferably a 30% decrease, more preferably a 40% decrease, yet morepreferably a 50% decrease of the IRLS Rating Scale Score.

In an embodiment, the amount of R(+)-N-propargyl-1-aminoindan or of thepharmaceutically acceptable salt thereof may be from 0.01 mg to 20 mgper day. By 0.01 mg to 20 mg it is meant that all hundredth, tenth andinteger unit amounts within the range are specifically disclosed as partof the invention. Thus, 0.02, 0.03 . . . 0.09; 0.1, 0.2 . . . 0.9; 1, 2. . . 19 mg unit amounts are included as embodiments of this invention.

In a further embodiment, the therapeutically effective amount ofR(+)-N-propargyl-1-aminoindan or of the pharmaceutically acceptable saltthereof may be from 0.5 mg to 5 mg per day.

In a specific embodiment, the amount may be 1.0 mg. By 0.5 mg to 5 mg itis meant that all tenth and integer unit amounts within the range arespecifically disclosed as part of the invention. Thus, 0.6, 0.7 . . .0.9; 1, 2 . . . 4 mg unit amounts are included as embodiments of thisinvention.

In an embodiment, a dose of R(+)-N-propargyl-1-aminoindan or of thepharmaceutically acceptable salt thereof may be administered 1 to 4times a day.

In a further embodiment, a dose of R(+)-N-propargyl-1-aminoindan or ofthe pharmaceutically acceptable salt thereof may be administered once aday.

Furthermore, an evening dose of R(+)-N-propargyl-1-aminoindan or of thepharmaceutically acceptable salt thereof may be administered to asubject 1 to 3 hours before the subject goes to bed.

Yet furthermore, a second dose is administered to the subject 3 to 7hours before the evening dose.

In another embodiment, a dose of R(+)-N-propargyl-1-aminoindan or of thepharmaceutically acceptable salt thereof is administered to the subjectat 3 to 7 hour intervals throughout the day.

In an embodiment, the administration is ofR(+)-N-propargyl-1-aminoindan.

In a further embodiment, the administration is of the pharmaceuticallyacceptable salt of R(+)-N-propargyl-1-aminoindan.

The pharmaceutically acceptable salt of the methods may be esylate,mesylate, sulfate or tartrate.

In a specific embodiment, the pharmaceutically acceptable salt may bemesylate.

In a further embodiment, the therapeutically effective amount ofR(+)-N-propargyl-1-aminoindan mesylate may be 1.66 mg per day.

1 mg of the base compound R(+)-N-propargyl-1-aminoindan amounts to 1.66mg of R(+)-N-propargyl-1-aminoindan mesylate.

In an embodiment, the administration may be oral, parenteral, rectal ortransdermal administration.

In a further embodiment of the invention, the methods further compriseadministration of carbidopa, levodopa, pergolide, pramipexole,oxycodone, clonazepam, carbamazepine, gabapentin, valproate, ropiniroleor clonidin.

In an embodiment, the administration of R(+)-N-propargyl-1-aminoindan orthe salt substantially precedes the administration of any of carbidopa,levodopa, pergolide, pramipexole, oxycodone, clonazepam, carbamazepine,gabapentin, valproate, ropinirole or clonidin.

In a further embodiment, the administration ofR(T)-N-propargyl-1-aminoindan or the salt is contemporaneous with theadministration of any of carbidopa, levodopa, pergolide, pramipexole,oxycodone, clonazepam, carbamazepine, gabapentin, valproate, ropiniroleor clonidin.

The R(+)-N-propargyl-1-aminoindan or the pharmaceutically acceptablesalt thereof may be in a pharmaceutical composition when used in themethods.

In an embodiment, the pharmaceutical composition is in tablet form.

In an embodiment, the pharmaceutical composition is in a form suitablefor transdermal administration.

In an embodiment, the pharmaceutical composition is in a form suitablefor sublingual administration.

The subject invention also provides a pharmaceutical compositioncomprising in unit dosage form R(+)-N-propargyl-1-aminoindan or apharmaceutically acceptable salt thereof and at least one of pergolide,pramipexole, oxycodone, clonazepam, carbamazepine, gabapentin,valproate, ropinirole or clonidin.

The subject invention also provides a pharmaceutical compositioncomprising in unit dosage form R(+)-N-propargyl-1-aminoindan or apharmaceutically acceptable salt thereof and pramipexole.

In an embodiment, the amount of R(+)-N-propargyl-1-aminoindan or of thepharmaceutically acceptable salt thereof is from 0.5 mg to 5 mg.

In a further embodiment, the amount of R(+)-N-propargyl-1-aminoindan is1 mg.

In a further embodiment, the R(+)-N-propargyl-1-aminoindan is thepharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindan.

In a further embodiment, the pharmaceutically acceptable salt isesylate, mesylate, sulfate or tartrate.

In a further embodiment, the pharmaceutically acceptable salt ismesylate.

In a further embodiment, the amount of R(+)-N-propargyl-1-aminoindanmesylate is 1.66 mg.

In a further embodiment, the amount of pramipexole is from 0.125 mg to0.6 mg.

In a further embodiment, the amount of pramipexole is from 0.375 mg to6.0 mg.

In a further embodiment, the amount of pramipexole is 0.6 mg.

In a further embodiment, the pramipexole is in a pharmaceuticallyacceptable salt form.

In a further embodiment, the pharmaceutically acceptable salt form ispramipexole dihydrochloride.

In a further embodiment, the amount of pramipexole dihydrochloride is0.6 mg.

In a further embodiment, the amount of pramipexole dihydrochloride is0.75 mg.

In a further embodiment, the amount of pramipexole is from 0.125 mg to0.6 mg.

In a further embodiment, the amount of pramipexole is from 0.375 mg to6.0 mg.

In a further embodiment, the amount of pramipexole is 0.6 mg.

In a further embodiment, the pramipexole is in a pharmaceuticallyacceptable salt form.

In a further embodiment, the pharmaceutically acceptable salt form ispramipexole dihydrochloride.

In a further embodiment, the amount of pramipexole dihydrochloride is0.6 mg.

In a further embodiment, the amount of pramipexole dihydrochloride is0.75 mg.

The subject invention also provides a pharmaceutical composition for usein the treatment of, or alleviation of symptoms of, Restless LegsSyndrome, which comprises a therapeutically effective amount ofR(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier.

The subject invention also provides use of R(+)-N-propargyl-1-aminoindanor a pharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of, or alleviation of symptoms of, RestlessLegs Syndrome. Such use can have the same embodiments as thosespecifically disclosed herein in the context of a method.

The present invention thus provides the R-(+)-enantiomer ofN-propargyl-1-aminoindan [“R(+)PAI” ] of the formula (I):

and pharmaceutically acceptable acid additions salts thereof for thetreatment of human patients for Restless Legs Syndrome (“RLS”). Thepresent invention also provides pharmaceutical compositions comprisingthe compound R(+)PAI, their preparations and methods of treatment of RLSwith the pharmaceutical compositions.

The subject invention also provides a method for the treatment of RLSwith rasagiline, wherein, the patient has previously been diagnosed andtreated for RLS and developed symptoms of augmentation, i.e. a commonconsequence of long term treatment in which the symptoms of RLS becomemore severe, occur earlier in the evening, and spread to other parts ofthe body.

Rasagiline is the INN (International Nonproprietary Name) and USAN(United States Adopted Name) of the chemical substanceR-(+)-N-propargyl-1-aminoindan.

R(+)PAI may be obtained by optical resolution of racemic mixtures of Rand S-enantiomer of N-propargyl-1-aminoindan (PAI). Such a resolutioncan be accomplished by any conventional resolution method, well known toa person skilled in the art, such as those described in “Enantiomers,Racemates and Resolutions” by J. Jacques, A. Collet and S. Wilen, Pub.John Wiley & Sons, N.Y., 1981. For example, the resolution may becarried out by preparative chromatography on a chiral column. Anotherexample of a suitable resolution method is the formation ofdiastereomeric salts with a chiral acid such as tartaric, malic,mandelic acid or N-acetyl derivatives of amino acids, such as N-acetylleucine, followed by recrystallisation to isolate the diastereomericsalt of the desired R enantiomer.

The racemic mixture of R and S enantiomers of PAI may be prepared, e.g.as described in WO095/11016. The racemic mixture of PAI can also beprepared by reacting l-chloroindan or 1-bromoindan with propargylamine.Alternatively, this racemate may be prepared by reacting propargylaminewith 1-indanone to form the corresponding imine, followed by reductionof the carbon-nitrogen double bond of the imine with a suitable agent,such as sodium borohydride.

In accordance with this invention, R(+)PAI can also be prepared directlyfrom the optically active R-enantiomer of l-aminoindan by reaction withpropargyl bromide or propargyl chloride in the presence of an organic orinorganic base and optionally in the presence of a suitable solvent. Apreferred method of preparation of the aforementioned compound is thereaction between R-1-aminoindan with propargyl chloride using potassiumbicarbonate as a base and acetonitrile as solvent.

The compound R(+)PAI may be prepared as pharmaceutical compositionsparticularly useful for the treatment of RLS. Such compositions maycomprise the compound of R(+)PAI or pharmaceutically acceptable acidaddition salts thereof, together with pharmaceutically acceptablecarriers and/or excipients. In the practice of this invention,pharmaceutically acceptable salts include, but are not limited to, themesylate, maleate, fumarate, tartrate, hydrochloride, hydrobromide,esylate, p-tolunesulfonate, benzoate, acetate, phosphate and sulfatesalts.

The compound pramipexole is a non-ergoline dopamine agonist effective asan adjunct therapy to levodopa in the treatment of patients withadvanced Parkinson's disease experiencing motor effects. It is alsoeffective as a monotherapy in early Parkinson's disease patients whereit has shown improvement in daily living and motor symptoms. Pramipexolehas been determined to act at dopamine D2 receptors, specifically atpresynaptic dopamine D2 autoreceptors and postsynaptic dopamine D2receptors. (Dooley M. et al., Pramipexole: A Review of Its Use in theManagement of Early and Advanced Parkinson's Disease, Drugs Aging, June1998, 12(6):495-514.

Pramipexole may be administered from 0.375 to 6.0 mg/day and in unitdosage from 0.125 to 1.5 mg. Pramipexole may be administered orally,inraperitoneally, subcutaneously or intravenously. (Dooley M. et al.,Pramipexole: A Review of Its Use in the Management of Early and AdvancedParkinson's Disease, Drugs Aging, June 1998, 12(6):495-514.

Pramipexole may be in the form of pramipexole base. In the practice ofthis invention, a pharmaceutically acceptable salt form of pramipexoleincludes pramipexole dihydrochloride. (Dooley M. et al., Pramipexole: AReview of Its Use in the Management of Early and Advanced Parkinson'sDisease, Drugs Aging, June 1998, 12(6):495-514.

Pramipexole may be initially administered at a dosage which is graduallyincreased until symptoms are relieved. (Dooley M. et al., Pramipexole: AReview of Its Use in the Management of Early and Advanced Parkinson'sDisease, Drugs Aging, June 1998, 12(6):495-514.

Pramipexole may be administered 3 times daily. (Dooley M. et al.,Pramipexole: A Review of Its Use in the Management of Early and AdvancedParkinson's Disease, Drugs Aging, June 1998, 12(6):495-514.

The compositions may be prepared as medicaments to be administeredorally, parenterally, rectally or transdermally. Suitable forms for oraladministration include tablets, compressed or coated pills, dragees,sachets, hard or soft gelatin capsules, sublingual tablets, syrups andsuspensions; for parenteral administration the invention providesampoules or vials that include an aqueous or non-aqueous solution oremulsion; for rectal administration there are provided suppositorieswith hydrophilic or hydrophobic vehicles; and for topical application asointments and transdermal delivery there are provided suitable deliverysystems as known in the art.

Specific examples of pharmaceutical acceptable carriers and excipientsthat may be used to formulate oral dosage forms of the present inventionare described, e.g., in U.S. Pat. No. 6,126,968 to Peskin et al., issuedOct. 3, 2000. Techniques and compositions for making dosage forms usefulin the present invention are described-in the following references: 7Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors,1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981);Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976);Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company,Easton, Pa., 1985); Advances in Pharmaceutical Sciences (DavidGanderton, Trevor Jones, Eds., 1992); Advances in PharmaceuticalSciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds.,1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugsand the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs andthe Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); DrugDelivery to the Gastrointestinal Tract (Ellis Horwood Books in theBiological Sciences. Series in Pharmaceutical Technology; J. G. Hardy,S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and thePharmaceutical Sciences Vol 40 (Gilbert S. Banker, Christopher T.Rhodes, Eds.).

Tablets may contain suitable binders, lubricants, disintegrating agents,coloring agents, flavoring agents, flow-inducing agents, and meltingagents. For instance, for oral administration in the dosage unit form ofa tablet or capsule, the active drug component can be combined with anoral, non-toxic, pharmaceutically acceptable, inert carrier such aslactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose,dicalcium phosphate, calcium sulfate, mannitol, sorbitol,microcrystalline cellulose and the like. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornstarch, natural and synthetic gums such as acacia, tragacanth, or sodiumalginate, povidone, carboxymethylcellulose, polyethylene glycol, waxes,and the like. Lubricants used in these dosage forms include sodiumoleate, sodium stearate, sodium benzoate, sodium acetate, sodiumchloride, stearic acid, sodium stearyl fumarate, talc and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, croscarmellose sodium, sodium starchglycolate and the like.

Rasagiline mesylate in a 1 mg tablet is commercially available for usein Parkinson's disease treatment as Azilect® from Teva PharmaceuticalIndustries, Ltd. (Petach Tikva, Israel) and H. Lundbeck A/S (Copenhagen,Denmark). See, also AZILECT®, Physician's Desk Reference (2006), 60^(th)Edition, Thomson Healthcare. The cognitive and behavioral adverse eventsof hallucinations, confusion, depression, somnolence and other sleepdisorders in subjects treated with Azilect® are few and do not exceedthe incidence seen in subjects receiving placebo by more than 3 percent.(Parkinson Study Group, Tyramine Challenge to Assess the Safety ofRasagiline Monotherapy in a Placebo-Controlled Multicenter Trial forEarly Parkinson's Disease (The TEMPO Study), Neurology, 2001, 56:A345)The most commonly reported adverse events in rasagiline-treated subjectsare pain, headache and dizziness. Side effects typically associated withother dopaminergic medications, such as hallucinations, somnolence,edema, nausea, vomiting, and diarrhea, are infrequently reported inrasagiline-treated subjects. (Stern et al., Double-Blind, Randomized,Controlled Trial of Rasagiline as Monotherapy in Early Parkinson'sDisease Patients, Mov. Disord., 2004, 19(8):916-923)

R(+)PAI compositions may be used alone to treat RLS, or alternatively,they may be used as an adjunct to existing RLS treatments. R(+)PAI maybe administered at different times and separate from other RLStreatments, or as a combined pharmaceutical composition of R(+)PAI withat least one of carbidopa, levodopa, pergolide, pramipexole, oxycodone,clonazepam, carbamazepine, gabapentin, valproate, ropinirole orclonidin. Thus, for example, a pharmaceutical composition for oral usein the form of tablets or capsules may compriseR(+)-N-propargyl-1-aminoindan, Levodopa, and a decarboxylase inhibitor.Such a composition may comprise 0.01-20 mg ofR(+)-N-propargyl-1l-aminoindan, 50-100 mg of Levodopa, and 12.5-50 mg ofbenserazide.

The preferred dosages of R(+)PAI in any of the disclosed compositionsmay be within the following ranges: for oral or suppository formulations0.01-20 mg per dosage unit to be taken daily and more preferably 0.5-5mg per dosage unit to be taken daily may be used; and for injectableformulations 0.05-10 mg/ml per dosage unit to be taken daily and morepreferably 0.5-3 mg/ml per dosage unit to be taken daily may be used.

By 0.01-20 mg it is meant that all hundredth, tenth and integer unitamounts within the range are specifically disclosed as part of theinvention. Thus, 0.02, 0.03 . . . 0.09; 0.1, 0.2 . . . 0.9; and 1, 2 . .. 19 mg unit amounts are included as embodiments of this invention.

R(+)PAI is effective and suitable for use in the treatment of RLS, bothalone and in combination with other RLS treatments.

Furthermore, unlike several known treatments of RLS, the use ofrasagiline as the active ingredient for treating RLS improves thesubject's condition without causing undesirable side effects. Thesubject is a human subject.

EXPERIMENTAL DETAILS Example 1

R(+)-N-propargyl-1-aminoindan mesylate 3.12 mg/tablet Mannitol 62.5mg/tablet Maltodextrin (Maltrin 150) 36.0 mg/tablet Croscarmellosesodium (Ac-Di-Sol)  2.1 mg/tablet Talc  1.5 mg/tablet

Example 2

R(+)-N-propargyl-1-aminoindan mesylate 1.56 mg/tablet Mannitol 79.14mg/tablet  Starch 10.0 mg/tablet Pregelatinized starch 10.0 mg/tabletColloidal silicon dioxide  0.6 mg/tablet Talc  2.0 mg/tablet Stearicacid  2.0 mg/tablet

Example 3

R(+)-N-propargyl-1-aminoindan mesylate 3.12 mg/tablet Mannitol 76.58mg/tablet  Starch 10.0 mg/tablet Pregelatinized starch 10.0 mg/tabletColloidal silicon dioxide  0.6 mg/tablet Citric acid  1.0 mg/tablet Talc 2.0 mg/tablet

Example 4

R(+)-N-propargyl-1-aminoindan mesylate 3.12 mg/tablet Mannitol 69.88mg/tablet  Lactose (hydrous) 14.0 mg/tablet Starch 14.0 mg/tabletGlyceryl Behenate (Compitrol 888 ATO)  2.0 mg/tablet

Example 5

R(+)-N-propargyl-1-aminoindan mesylate 3.12 mg/tablet Mannitol 77.28mg/tablet  Starch 10.0 mg/tablet Starch STA-RX 1500 10.0 mg/tabletColloidal silicon dioxide, Aerosil  0.6 mg/tablet Hydrogenated vegetabletype I  2.0 mg/tablet (Sterotex Dritex)

Example 6—Rat Model of RLS

6-hydroxydopamine is an agent that selectively disrupts or destroyscatecholaminergic systems. Thus, stereotaxic bilateral 6-hydroxydopaminelesions into the nucleus of dopaminergic diencephalic spinal neurons(All) are performed to effect behavior consistent, although notspecific, with what would be expected in a rat model of RLS. (Ondo W. G.et al., Clinical Correlates of 6-Hydroxydopamine Injections into AllDopaminergic Neurons in Rats: A Possible Model for Restless LegSyndrome, Mov. Disord., 2000, 15(1):154-8)

Multiple blindly-rated video epochs demonstrate an increased averagenumber of standing episodes and increased total standing time butsimilar total sleep time in lesioned rats when compared with controlrats. However, treatment of the lesioned rats with R(+)PAI mesylateresults in fewer standing episodes and less total standing time whencompared with untreated lesioned rats.

Example 7—RLS Model Spontaneously Occurring During Sleep of Rats

Periodic limb movements in sleep (PLMS) are often associated with RLS.In a group of old rats 16-20 months, sleep-wake behavior is recorded andhindlimb movements are detected by means of a magneto-inductive deviceduring two 12-h light periods (Baier P. C. et al., Assessment ofspontaneously occurring periodic limb movements in sleep in the rat, J.Neurol. Sci. 2002; 198(1-2): 71-77). Periodic hindlimb movements (PHLM)during nonrapid eye movement sleep (NREM) are identified according tomodified human criteria in some of the rats, which are then selected forthe rasagiline study. Half the rats are treated daily with rasagilinewhile the other half receive vehicle. Incidence of PHLM is determinedfor 3 consecutive nights, beginning 7 days after onset of treatment. Itis demonstrated that rasagiline-treated rats have significantly fewerPHLM than vehicle-treated rats.

Example 8

The 1 mg tablet of R(+)PAI mesylate is investigated inplacebo-controlled, double-blind, randomized clinical tests covering ina study adult patients who are suffering from moderate to severe primaryRestless Legs Syndrome.

Randomization in terms of gender, age and severity of prior illnesses isreasonably balanced. Patients with RLS secondary to other conditions(e.g., pregnancy, renal failure, and anemia) are excluded.

After gradual and complete termination of any preceding L-dopa treatmentand a break in the therapy (washout) the patients are treated withR(+)PAI.

Over a treatment period of days the patients of one group are treatedwith a 0.5 mg dosage and the patients of another group are treated with1 mg. For a comparison the patients in the placebo group are treatedwith a placebo.

Severity of symptoms is measured with a rating scale developed by theInternational Restless Legs Syndrome Study Group(“IRLSSG”)(http://www.irlssg.org/). Use of the scale is common forclinical assessment, research and therapeutic trials with RLS. Theoverall IRLSSG rating is derived from the individual values discussedbelow.

First, an initial starting value is determined for each patientparticipating in the study. This is done by adding up the individualIRLSSG parameter values as of Day 0, i.e. before treatment. Over thecourse of treatment the IRLSSG values are compared with the startingvalue and any changes from that starting value are recorded. Finally,the average improvement of the IRLSSG value over the starting value isdetermined by calculating the average of all test subjects. Theresulting value is called CAS—(complete analysis set) randomized averagechange from the starting value of the overall IRLSSG rating. The term“randomized” indicates that in terms of their different prespecifieddosages the patients are subjected to prior double-blind randomization.

Results

Between the starting value and that established after treatment, asignificant improvement of the IRLSSG values is recorded in comparisonwith the placebo group.

At the end of the treatment both patient groups report that subjectivesymptoms such as tingling, cramps and pain in the legs, restlessness inthe legs during the night, and difficulties falling or remaining asleepeither disappear or diminish to a tolerable minimum.

The patients also report that the treatment does not or only to a veryminimal extent causes any hallucinations, somnolence, edema, nausea,vomiting or diarrhea.

Accordingly, R(+)PAI is well tolerated and safe and leads to a distinctclinical improvement in patients in a moderate to severe stage of RLS.

An improvement of the IRLSSG value of 2 points compared to a placebo canbe considered a success. An improvement by over 3 or 6 and more ratingunits constitutes an all the more significant therapeutic advance and istherefore the preferred objective of this invention.

Example 9

This was the first clinical study in which rasagiline was administeredto RLS subjects. The dosage regimen of 1 mg/day rasagiline was chosenbased on the optimal dosage regimen for the symptomatic treatment of PD.However, smaller doses than those required for the treatment of PD areexpected to be efficacious in the treatment of RLS. Therefore, in theevent that a subject could not tolerate the 1 mg daily dose ofrasagiline, a daily dose of 0.5 mg rasagiline was permitted. Rasagilinewas administered orally as a tablet. Both the 1 mg and 0.5 mg rasagilinetablets were beveled round tablets, flat, white to off-white, scored onone side, plain on the other side. Teva Pharmaceutical Industries Ltd.was responsible for the manufacture and primary packaging of studymedications according to current Good Manufacturing Practice (cGMP)principles and guidelines applicable to investigational medicinalproducts.

Schedule of Activities

Visit Week No. Week-2^(a) Week 0 Week 12/Early Unscheduled (screening)(baseline) Week 2 ± 4 Week 4 ± 4 Week 8 ± 4 Termination ± 4 Visit^(b)Informed consent X Inclusion/Exclusion criteria X X Medical history XConcomitant medications X X X X X X X IRLS X X X X X X Sleep Scale X X XX CGI-I X X X X RLS Quality of Life Questionnaire X X X X Adverse eventsX X X X X X AE follow up X Laboratory test including β-hCG^(c) X X XVital signs^(d) X X X X X X X ECG X X X Dermatological evaluation X X XStudy termination X Retrieve study drug and assess X X X X X complianceDispense study drug X X X X Xa) The maximal interval between the screening and baseline visits shouldbe 14 days. If, however, results from screening procedures are stillpending after 14 days from the screening visit and the investigator hasto wait until all results are available before determining a subject'seligibility, the interval between the screening and baseline visits mayextend up to 21 days.b) Procedures during an unscheduled visit are optional, except vitalsigns.c) Pregnancy test relevant to women of childbearing potential onlyd) Including weight and height at screening and weight at Visit Week8/Early Termination

IRLS (International Restless Legs Scale)

The IRLS scale is comprised of 10 items designed to assess the severityof sensory and motor symptoms, sleep disturbance, daytime somnolence,and impact on activities of daily living and mood associated with RLS.All items receive a grade in the range 0 to 4 (0=absence of a problem,4=very severe problem) giving a maximum score of 40.

The investigator scored subjects on the IRLS at all scheduled studyvisits. The primary efficacy endpoint was based on the change frombaseline to weeks 2, 4, and 8 in IRLS scores.

IRLS Scale

Each of 10 items were graded on a scale between 0 and 4 where 0 denotesthe absence of a problem, and 4 a very severe problem. Table 1 shows theresults; a low score indicates the absence of a problem and a high scoreindicates a very severe problem.

TABLE 1 Descriptive Statistics of IRLS Rating Scale and Change fromBaseline Over Time IRLS Total Me- IRLS Total (Absolute Change) IRLSTotal (Percent Change) Week N Mean SD Min dian Max N Mean SD Min MedianMax N Mean SD Min Median Max BASE- 2 32.00 8.49 26.00 32.00 38.00 2 0.000.00 0.00 0.00 0.00 2 0.00 0.00 0.00 0.00 0.00 LINE VISIT 2 29.00 12.7320.00 29.00 38.00 2 −3.00 4.24 −6.00 −3.00 0.00 2 −11.54 16.32 −23.08−11.54 0.00 WEEK 2 VISIT 2 25.50 17.68 13.00 25.50 38.00 2 −6.50 9.19−13.00 −6.50 0.00 2 −25.00 35.36 −50.00 −25.00 0.00 WEEK 4 VISIT 1 12.0012.00 12.00 12.00 1 −14.00 −14.00 −14.00 −14.00 1 −53.85 −53.85 −53.85−53.85 WEEK 8

Clinical Global Impression-Global Improvement (CGI-I)

The CGI-I scale is a single item scale on which the investigator rated asubject's symptoms as very much improved, much improved, minimallyimproved, not changed, minimally worse, much worse, or very much worse.Subjects were scored on this scale at weeks 2, 4, and 8. The mean scoreat each of these time points was calculated as a secondary efficacyendpoint. Table 2 shows the results of the CGI-I Rating Scale. Subjectsare scored on a scale of 1-7, where 1 indicates the subject's symptomsare very much improved and 7 indicates the subject's symptoms are verymuch worse.

TABLE 2 Descriptive Statistics of CGI-I Rating Scale CGI-I Total Week NMean SD Min Median Max VISIT WEEK 2 2 3.50 0.71 3.00 3.50 4.00 VISITWEEK 4 2 3.50 2.12 2.00 3.50 5.00 VISIT WEEK 8 1 1.00 1.00 1.00 1.00

RLS QoL Questionnaire

The Restless Leg Syndrome Quality of Life questionnaire (RLS QoL)assesses the impact of RLS on daily life, emotional well-being, sociallife and work life. It is an 18-item questionnaire with a total scoreranging 0 to 100. Table 3 shows the results of this questionnaire. Thelower the score, the greater the impact of RLS on quality of life.

TABLE 3 Descriptive Statistics of IRLS QoL Rating Scale and Change fromBaseline Over Time IRLS QoL Total IRLS QoL Total (Absolute Change) IRLSQoL Total (Percent Change) Week N Mean SD Min Median Max N Mean SD MinMedian Max N Mean SD Min Median Max BASELINE 2 46.25 30.05 25.00 46.2567.50 2 0.00 0.00 0.00 0.00 0.00 2 0.00 0.00 0.00 0.00 0.00 VISIT WEEK 42 62.92 41.84 33.33 62.92 92.50 2 16.67 11.79 8.33 16.67 25.00 2 35.192.62 33.33 35.19 37.04 VISIT WEEK 8 1 92.50 92.50 92.50 92.50 1 25.0025.00 25.00 25.00 1 37.04 37.04 37.04 37.04

(Abetz L. et al. Validation of the restless legs syndrome quality oflife questionnaire. Value in Health, 2005; 8(2): 157-167)

The RLS QoL questionnaire was completed by the investigator at thebaseline and Week 4, and 8 visits. The change from baseline to eachpost-baseline study visit was calculated as an additional efficacyendpoint.

Sleep Scale:

The Sleep Scale is a 12-item scale that provides a comprehensive viewacross almost all dimensions of sleep including daytime somnolence,sleep disturbance, sleep adequacy and sleep quantity. The investigatorscored subjects on this scale at the baseline and Week 4, and 8 visits.The change from baseline to each post-baseline study visit wascalculated as a secondary efficacy endpoint. (Hays, R. D. & Steward, A.L. (1992). Sleep measures. In A. L. Stewart & J. E. Ware (eds.),Measuring functioning and well-being: The Medical Outcomes Studyapproach (pp. 235-259), Durham, N.C.: Duke University Press.

Tables 4-12 show the results of the Sleep Rating Scale and change frombaseline over time for each of the 9 dimensions scored by the SleepRating Scale. N is the number of participants in the study. A low scoreindicates the absence of problems and a high score indicates a verysevere problem.

TABLE 4 Descriptive Statistics of Sleep Rating Scale and Change fromBaseline Over Time Sleep Disturbance Scale Me- Sleep Disturbance(Absolute Change) Sleep Disturbance (Percent Change) Week N Mean SD Mindian Max N Mean SD Min Median Max N Mean SD Min Median Max BASE- 2 41.255.30 37.50 41.25 45.00 2 0.00 0.00 0.00 0.00 0.00 2 0.00 0.00 0.00 0.000.00 LINE VISIT 2 33.75 15.91 22.50 33.75 45.00 2 −7.50 10.61 −15.00−7.50 0.00 2 −20.00 28.28 −40.00 −20.00 0.00 WEEK 4 VISIT 1 21.25 21.2521.25 21.25 1 −16.25 −16.25 −16.25 −16.25 1 −43.33 −43.33 −43.33 −43.33WEEK 8

TABLE 5 Descriptive Statistics of Sleep Rating Scale and Change fromBaseline Over Time Snoring Scale Sleep Snoring (Absolute Change) SleepSnoring (Percent Change) Week N Mean SD Min Median Max N Mean SD MinMedian Max N Mean SD Min Median Max BASELINE 2 40.00 56.57 0.00 40.0080.00 2 0.00 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 VISIT WEEK 240.00 56.57 0.00 40.00 80.00 2 0.00 0.00 0.00 0.00 0.00 1 0.00 0.00 0.000.00 4 VISIT WEEK 1 100.00 100.00 100.00 100.00 1 20.00 20.00 20.0020.00 1 25.00 25.00 25.00 25.00 8

TABLE 6 Descriptive Statistics of Sleep Rating Scale and Change fromBaseline Over Time Sleep Short of Breath (Absolute Sleep Short of Breath(Percent Short of Breath Scale Change) Change) Week N Mean SD Min MedianMax N Mean SD Min Median Max N Mean SD Min Median Max BASE- 2 0.00 0.000.00 0.00 0.00 2 0.00 0.00 0.00 0.00 0.00 0 LINE VISIT 2 0.00 0.00 0.000.00 0.00 2 0.00 0.00 0.00 0.00 0.00 0 WEEK 4 VISIT 1 0.00 0.00 0.000.00 1 0.00 0.00 0.00 0.00 0 WEEK 8

TABLE 7 Descriptive Statistics of Sleep Rating Scale and Change fromBaseline Over Time Sleep Adequacy Sleep Adequacy (Absolute Change) SleepAdequacy (Percent Change) Week N Mean SD Min Median Max N Mean SD MinMedian Max N Mean SD Min Median Max BASELINE 2 40.00 28.28 20.00 40.0060.00 2 0.00 0.00 0.00 0.00 0.00 2 0.00 0.00 0.00 0.00 0.00 VISIT 255.00 49.50 20.00 55.00 90.00 2 15.00 21.21 0.00 15.00 30.00 2 25.0035.36 0.00 25.00 50.00 WEEK 4 VISIT 1 100.00 100.00 100.00 100.00 140.00 40.00 40.00 40.00 1 66.67 66.67 66.67 66.67 WEEK 8

TABLE 8 Descriptive Statistics of Sleep Rating Scale and Change fromBaseline Over Time Somnolence Scale Sleep Somnolence (Absolute Change)Sleep Somnolence (Percent Change) Week N Mean SD Min Median Max N MeanSD Min Median Max N Mean SD Min Median Max BASELINE 2 40.00 37.71 13.3340.00 66.67 2 0.00 0.00 0.00 0.00 0.00 2 0.00 0.00 0.00 0.00 0.00 VISITWEEK 2 40.00 47.14 6.67 40.00 73.33 2 −0.00 9.43 −6.67 −0.00 6.67 2−20.00 42.43 −50.00 −20.00 10.00 4 VISIT WEEK 1 13.33 13.33 13.33 13.331 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 8

TABLE 9 Descriptive Statistics of Sleep Rating Scale and Change fromBaseline Over Time Sleep Problems Index I Sleep Problems Index I(Absolute Me- Change) Sleep Problems Index I (Percent Change) Week NMean SD Min dian Max N Mean SD Min Median Max N Mean SD Min Median MaxBASE- 2 33.33 23.57 16.67 33.33 50.00 2 0.00 0.00 0.00 0.00 0.00 2 0.000.00 0.00 0.00 0.00 LINE VISIT 2 26.67 33.00 3.33 26.67 50.00 2 −6.679.43 −13.33 −6.67 0.00 2 −40.00 56.57 −80.00 −40.00 0.00 WEEK 4 VISIT 10.00 0.00 0.00 0.00 1 −16.67 −16.67 −16.67 −16.67 1 −100.00 −100.00−100.00 −100.00 WEEK 8

TABLE 10 Descriptive Statistics of Sleep Rating Scale and Change fromBaseline Over Time Sleep Problems Index II Sleep Problems Index II(Absolute Sleep Problems Index II (Percent Me- Change) Change) Week NMean SD Min dian Max N Mean SD Min Median Max N Mean SD Min Median MaxBASE- 2 40.56 18.07 27.78 40.56 53.33 2 0.00 0.00 0.00 0.00 0.00 2 0.000.00 0.00 0.00 0.00 LINE VISIT 2 33.89 27.50 14.44 33.89 53.33 2 −6.679.43 −13.33 −6.67 0.00 2 −24.00 33.94 −48.00 −24.00 0.00 WEEK 4 VISIT 111.67 11.67 11.67 11.67 1 −16.11 −16.11 −16.11 −16.11 1 −58.00 −58.00−58.00 −58.00 WEEK 8

TABLE 11 Descriptive Statistics of Sleep Rating Scale and Change fromBaseline Over Time Sleep Quantity (raw score) Sleep Quantity (AbsoluteChange) Sleep Quantity (Percent Change) Week N Mean SD Min Median Max NMean SD Min Median Max N Mean SD Min Median Max BASELINE 1 7.00 7.007.00 7.00 1 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 VISIT 1 7.00 7.007.00 7.00 1 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 WEEK 4 VISIT 17.00 7.00 7.00 7.00 1 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 WEEK 8

TABLE 12 Descriptive Statistics of Sleep Rating Scale and Change fromBaseline Over Time Optimal Sleep Scale Optimal Sleep (Absolute Change)Optimal Sleep (Percent Change) Week N Mean SD Min Median Max N Mean SDMin Median Max N Mean SD Min Median Max BASELINE 1 1.00 1.00 1.00 1.00 10.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 VISIT 1 1.00 1.00 1.00 1.00 10.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 WEEK 4 VISIT 1 1.00 1.00 1.001.00 1 0.00 0.00 0.00 0.00 1 0.00 0.00 0.00 0.00 WEEK 8

CONCLUSION

To date, 2 subjects have been enrolled in this open label pilot study ofrasagiline's efficacy in Restless Legs Syndrome. These subjects had amean baseline IRLS Rating Scale score of 32. After 2 weeks the meanscore had decrease to 29. At 4 weeks, one subject had a score of 13(indicating a 50% decrease from baseline). Another subject discontinuedparticipation in the study, at week 4, with a score of 38, unchangedfrom this subject's baseline score. By 8 weeks, the remaining subject'sIRLS score had decreased to 12 (a 54% decrease from baseline).Additionally, by eight weeks this subject had indicated that the RLSsymptoms were “Very Much Improved” on the CGI-I rating scale. Also, byeight weeks this subject had an improvement of 37% in the IRLS Qualityof Life Questionnaire compared to baseline. In addition, by eight weeks,this subject had an improvement of 58% in the Sleep Problems Index IIstatistic measured as part of the Sleep Scale. In summary, in at least asubset of RLS patients, rasagiline has been shown to have a clinicallysignificant effect on the symptoms of RLS.

What is claimed is:
 1. A pharmaceutical composition comprising in unitdosage form R(+)-N-propargyl-1-aminoindan or a pharmaceuticallyacceptable salt thereof and at least one of pergolide, pramipexole,oxycodone, clonazepam, carbamazepine, gabapentin, valproate, ropiniroleor clonidin.